Cystic Fibrosis (CF)

There are late-stage, phase 2 clinical trials expected to yield new treatments for cystic fibrosis (CF) in the coming years. These include novel CF transmembrane conductance regulator (CFTR) modulators and CFTR correctors.¹  

VX-121 and Deutivacaftor (VX-561) Combination Therapy 

VX-121 is a CFTR corrector that allows for proper intracellular trafficking of mutant CFTR, allowing its incorporation into the cell membrane. Deutivacaftor (VX-561) functions similarly to ivacaftor (Kalydeco®) by potentiating the CFTR channel and allowing chloride transport across the cell membrane. Following satisfactory results from a phase 2 trial using triple therapy with VX-121/tezacaftor/VX-561 in adult patients with CF,² phase 3 trials have commenced and are currently enrolling patients. 

Combination therapy with VX-121/tezacaftor/deutivacaftor is being evaluated in a phase 3, randomized, quadruple-masked study (NCT05076149), which is currently in the recruiting phase and hopes to enroll 550 participants. The goal is to evaluate the efficacy and safety of this regimen in CF patients ≥12 years of age who are either homozygous for the F508del mutation, heterozygous for F508del and a gating mutation, heterozygous for F508del with a residual function mutation, or have at least 1 other triple-combination-responsive CFTR mutation and no F508del mutation. Participants will receive either VX-121/tezacaftor/deutivacaftor in the morning with no evening dose or elexacaftor/tezacaftor/ivacaftor in the morning and ivacaftor in the evening. The primary outcome measure is the absolute change in percentage predicted forced expiratory volume in 1 second (ppFEV1) from baseline to week 24. The study will also assess changes in sweat chloride levels through week 24. The expected completion date is February 2024.³ 

A second phase 3 study is also underway, which aims to evaluate the efficacy and safety of VX-121/tezacaftor/deutivacaftor in CF patients ≥12 years of age who are heterozygous for F508del and a minimal function mutation (NCT05033080). Participants will receive either VX-121/ tezacaftor/ivacaftor in the morning with no evening dose or elexacaftor/tezacaftor/ivacaftor in the morning and ivacaftor in the evening. The primary outcome measure is the absolute change in ppFEV1 from baseline to week 24, and the study will also assess changes in sweat chloride levels through week 24. It is expected to completed in January 2024.⁴

ABBV-3067 and ABBV-2222

ABBV-3067 is an investigational CFTR potentiator, and ABBV-2222 is an investigational CFTR corrector.¹ Both drugs are taken orally. A phase 2, randomized, placebo-controlled, quadruple-masked study is currently recruiting patients and aims to enroll 189 participants (NCT03969888). The study will evaluate the safety, tolerability, and efficacy of ABBV-3067 given alone or in combination with ABBV-2222 in adult CF patients who are homozygous for the F508del mutation. Participants will be grouped into 4 arms composed of 3 experimental groups and 1 placebo comparator group. Participants in the experimental groups will receive either ABBV-3067 + placebo or ABBV-3067 + ABBV-2222 at different dosages and will be compared to a control group receiving placebo. The primary outcome measure is the absolute change in ppFEV1 from baseline to day 29. The study will also assess changes in sweat chloride levels, absolute change in forced expiratory flow rate at mid-lung capacity, relative change in ppFEV1, relative change in forced expiratory flow at mid-lung capacity, and relative change in forced vital capacity through day 29. The estimated completion date is October 22, 2022.⁵

References

1. Promising drugs in clinical development for cystic fibrosis. News release. GlobalData Healthcare; September 16, 2021. Updated December 2, 2021.

2. A study to evaluate the safety and efficacy of VX-121 combination therapy in subjects with cystic fibrosis. ClinicalTrials.gov. April 11, 2019. Updated December 11, 2020. Accessed January 24, 2022. 

3. A study of VX-121 combination therapy in participants with cystic fibrosis (CF) who are homozygous for F508del, heterozygous for F508del and a gating (F/G) or residual function (F/RF) mutation, or have at least 1 other triple combination responsive (TCR) CFTR mutation and no F508del mutation. ClinicalTrials.gov. October 13, 2021. Updated January 11, 2022. Accessed January 24, 2022. 

4. A phase 3 study of VX-121 combination therapy in participants with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF). ClinicalTrials.gov. September 2, 2021. Updated January 11, 2022. Accessed January 24, 2022. 

5. A phase 2 study of ABBV-3067 alone and in combination with ABBV-2222. ClinicalTrials.gov. May 31, 2019. Updated January 11, 2022. Accessed January 24, 2022.

Reviewed by Hasan Avcu, MD, on 1/26/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.